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• W2949773807 abstract "Abstract Thrombin-derived C-terminal peptides (TCP) of about 2 kDa are present in wounds, where they exert anti-endotoxic functions. In an effort to elucidate the structural and molecular aspects of these functions, we here employ a combination of nuclear magnetic resonance spectroscopy (NMR), ellipsometry, fluorescence spectroscopy, circular dichroism (CD) measurements, and in silico multiscale modeling to define interactions and the bound conformation of a TCP generated by neutrophil elastase, HVF18 (HVFRLKKWIQKVIDQFGE) in complex with bacterial lipopolysaccharide (LPS). In contrast to the disordered state of HVF18 in aqueous solution, its binding to LPS leads to a structural transition, wherein the N- terminus of the peptide forms a unique ß-turn whilst the C-terminus becomes helical. In silico modelling and simulations demonstrated that HVF18, as well as related peptides, target the LPS-binding site of CD14, and this interaction was experimentally supported using microscale thermophoresis. Collectively, the results demonstrate the role of structural transitions in LPS complex formation as well as in CD 14 interaction, and provide a molecular explanation for the previously observed therapeutic effects of TCPs in experimental models of bacterial sepsis and endotoxin shock. Significance Thrombin-derived C-terminal peptides (TCPs) of various sizes are present in human wounds, where they bind bacteria as well as “free” lipopolysaccharide (LPS), and thereby reduce inflammation. In this work, employing a combination of cellular, biophysical and structural studies, combined with in silico multiscale modeling, we present the molecular structure of a TCP in association with LPS, and define a previously undisclosed interaction between TCPs and CD14. Further, we show that TCPs exhibit relatively weak but specific affinities, all in the μM range, to both LPS and CD14. These novel structural insights into the function of this class of host-defense molecules will facilitate rational design of novel “dual function” anti-infectives, which target both bacteria and inflammatory signaling." @default.
• W2949773807 created "2019-06-27" @default.
• W2949773807 creator A5001674990 @default.
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• W2949773807 date "2017-12-12" @default.
• W2949773807 modified "2023-10-17" @default.
• W2949773807 title "Structural basis for endotoxin neutralization and anti-inflammatory activity of thrombin-derived C-terminal peptides" @default.
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• W2949773807 doi "https://doi.org/10.1101/232876" @default.
• W2949773807 hasPublicationYear "2017" @default.
• W2949773807 type Work @default.
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